Systems and methods for modulation of pancreatic endocrine secretion and treatment of diabetes

ABSTRACT

Systems and methods for introducing one or more stimulating drugs and/or applying electrical stimulation to the pancreas and/or nerve fibers innervating the pancreas to treat or prevent diabetes and/or to modulate pancreatic endocrine secretions uses at least one system control unit (SCU) producing electrical pulses delivered via electrodes and/or producing drug infusion pulses, wherein the stimulating drug(s) are delivered via one or more pumps and infusion outlets.

The present application claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/252,626, filed Nov. 21, 2000, which applicationis incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention generally relates to drug delivery and electricalstimulation systems and methods, and more particularly relates toutilizing one or more devices to deliver electrical stimulation and/orone or more stimulating drugs for the modulation of pancreatic endocrinesecretion and as a treatment for diabetes.

BACKGROUND OF THE INVENTION

Twelve to fifteen million people in the United States suffer fromdiabetes mellitus (which is often, as herein, simply referred to asdiabetes). Diabetes is a syndrome characterized by disordered metabolismand inappropriately high levels of blood glucose, i.e., hyperglycemia.Diabetes is classified into two distinct types. Type 1, also known asInsulin-Dependent Diabetes Mellitus (IDDM), is believed to be due toautoimmune destruction of beta cells in the pancreas, which are the onlycells in the body that produce and secrete insulin. Type 1 occurs mostcommonly in juveniles but occasionally in adults. Type 2, also known asNon-Insulin-Dependent Diabetes Mellitus (NIDDM), is a milder form ofdiabetes that usually occurs in adults.

Up to about 10% of people with diabetes have type 1 diabetes, and aredependent on daily exogenous insulin. Insulin, a small protein, isdegraded when taken orally; thus, it must be administered parenterally.Thus, most patients take insulin through injection. An increasing numberare receiving insulin through a percutaneous pump, but this requiresexternal apparatus that must be worn continuously. A fully implantablepump is also available, requiring monthly visits to a physician torefill the pump. An inhaled version of insulin is under development.Additional treatment options are needed.

SUMMARY OF THE INVENTION

The invention disclosed and claimed herein provides modulation ofpancreatic endocrine secretion and treatment or prevention of diabetes,via one or a combination of systems and methods. Some systems andmethods of the present invention provide electrical stimulation ofpancreatic cells, and particularly of alpha and delta cells, as well asbeta cells. Stimulation to depolarize/hyperpolarize alpha and deltacells modulates the secretion of glucagon and somatostatin,respectively, which in turn affects the secretion of insulin by betacells. In addition, the present invention teaches hyperpolarization ofpancreatic beta cells, for inhibiting the secretion of insulin duringperiods of hypoglycemia. Further, the present invention teacheseffective frequencies for electrical stimulation, so that stimulation ofpancreatic islet cells is maximized while the stimulation of otherstructures is minimized.

Additional systems and methods taught herein provide electricalstimulation of autonomic nerves and/or ganglia innervating the pancreas,thereby modulating insulin and glucagon secretion. For example,stimulation to decrease the excitement of sympathetic input to thepancreatic beta cells will increase insulin production.

Other systems and methods of the present invention provide theapplication of a stimulating drug(s) alone or in combination withelectrical stimulation. These drugs may modulate the release of insulin,somatostatin, and glucagon. This invention also includes the possibilityof combining stimulation with medication released from an implantedreservoir (i.e., a drug pump).

Electrical and/or drug stimulation of specific sites innervating and/orwithin the pancreas, and the resulting changes in secretion of insulin,glucagon, and somatostatin, may have significant therapeutic benefit inthe control of diabetes. In addition, it is believed that 1) insulin andsomatostatin secretions induced by glucose are inhibited during SNSthrough alpha-adrenergic activation, 2) insulin and somatostatinsecretions are stimulated during SNS through beta-adrenergic activation,and 3) SNS-induced glucagon secretion occurs mainly throughalpha-adrenergic activation.

This invention may prove beneficial in cases of transplanted beta cells,wherein the cells have no innervation lo modulate insulin secretion.This invention may also prove beneficial in cases of blunted or absentresponse of endogenous pancreatic endocrine tissue to neuralstimulation. Additional potential (but not necessary) uses of thepresent invention include, but are not limited to, application todiabetes prevention, e.g., by inhibiting glucagon and/or somatostatinfrom attenuating the effects of insulin, possibly by decreasing glucagonand/or somatostatin plasma levels.

The invention is carried out via one or more system control units (SCUs)that apply electrical stimulation and/or one or more stimulating drugsto one or more predetermined stimulation sites. In some forms of SCUs,one or more electrodes are surgically implanted to provide electricalstimulation from an implantable signal/pulse generator (IPG) and/or oneor more infusion outlets and/or catheters are surgically implanted toinfuse drug(s) from an implantable pump. When necessary and/or desired,an SCU provides both electrical stimulation and one or more stimulatingdrugs. In other forms of an SCU, a miniature implantable neurostimulator(a.k.a., a microstimulator), such as a Bionic Neuron (also referred toas a BION® microstimulator), is implanted. Some forms of the disclosedsystems also include one or more sensors for sensing symptoms or otherconditions that may indicate a needed treatment.

The SCU may include a programmable memory for storing data and/orcontrol parameters. This allows stimulation and control parameters to beadjusted to levels that are safe and efficacious with minimaldiscomfort. Electrical and drug stimulation may be controlledindependently; alternatively, electrical and drug stimulation may becoupled, e.g., electrical stimulation may be programmed to occur onlyduring drug infusion.

According to some embodiments of the invention, the electrodes used forelectrical stimulation are arranged as an array on a thin implantablelead. The SCU may be programmed to produce either monopolar electricalstimulation, e.g., using the SCU case as an indifferent electrode, orbipolar electrical stimulation, e.g., using one of the electrodes of theelectrode array as an indifferent electrode. The SCU may include a meansof stimulating tissue or infusing a stimulating drug(s) eitherintermittently or continuously. Specific stimulation/infusion parametersmay provide therapy for, e.g., varying types and degrees of severity ofdiabetes.

The SCU used with the present invention possesses one or more of thefollowing properties, among other properties:

at least two electrodes for applying stimulating current to surroundingtissue and/or a pump and at least one outlet for delivering a drug ordrugs to surrounding tissue;

electronic and/or mechanical components encapsulated in a hermeticpackage made from biocompatible material(s);

an electrical coil inside the package that receives power and/or data byinductive or radio-frequency (RF) coupling to a transmitting coil placedoutside the body, avoiding the need for electrical leads to connectdevices to a central implanted or external controller;

means for receiving and/or transmitting signals via telemetry;

means for receiving and/or storing electrical power within the SCU; and

a form factor making the SCU implantable in a target area in the body.

The power source of the SCU is realized using one or more of thefollowing options, or the like:

(1) an external power source coupled to the SCU via a radio-frequency(RF) link;

(2) a self-contained power source made using any means of generation orstorage of energy, e.g., a primary battery, a replenishable orrechargeable battery, a capacitor, a supercapacitor; and/or

(3) if the self-contained power source is replenishable or rechargeable,a means of replenishing or recharging the power source, e.g., an RFlink, an optical link, or other energy-coupling link.

According to certain embodiments of the invention, an SCU operatesindependently. According to various embodiments of the invention, an SCUoperates in a coordinated manner with other implanted SCUs, otherimplanted devices, or with devices external to the patient's body.

According to several embodiments of the invention, an SCU incorporatesmeans of sensing the disorder or symptoms thereof, or other measures ofthe state of the patient. Sensed information may be used to control theelectrical and/or drug stimulation parameters of the SCU in a closedloop manner. According to some embodiments of the invention, the sensingand stimulating means are incorporated into a single SCU. According toseveral embodiments of the invention, the sensing means communicatessensed information to at least one SCU with stimulating means.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other aspects of the present invention will be moreapparent from the following more particular description thereof,presented in conjunction with the following drawings wherein:

FIG. 1 is a schematic of the autonomic nervous system;

FIG. 2 depicts the innervation of areas and structures in the vicinityof the pancreas;

FIG. 3A shows some of the nerves in the vicinity of the pancreas;

FIG. 3B is a view of some of the nerves in the vicinity of the pancreas,with the stomach reflected;

FIG. 3C is a view of some of the nerves in the vicinity of the pancreas,and more particularly, in the hiatal region;

FIGS. 4A, 4B, and 4C show some possible configurations of an implantablemicrostimulator of the present invention;

FIG. 5 depicts internal and external components of certain embodimentsof the invention;

FIG. 6 illustrates external components of various embodiments of theinvention; and

FIG. 7 depicts a system of implantable devices that communicate witheach other and/or with external control/programming devices.

Corresponding reference characters indicate corresponding componentsthroughout the several views of the drawings.

DETAILED DESCRIPTION OF THE INVENTION

The following description is of the best mode presently contemplated forcarrying out the invention. This description is not to be taken in alimiting sense, but is made merely for the purpose of describing thegeneral principles of the invention. The scope of the invention shouldbe determined with reference to the claims.

Insulin is released only by beta cells in pancreatic islets (i.e., smallisolated masses of one type of tissue within a different type), known asthe islets of Langerhans. Insulin is one of the endocrine systemsecretions (i.e., secretions that are distributed in the body by way ofthe bloodstream) of the islets of Langerhans, which help integrate andcontrol bodily metabolic activity. The islets also include alpha cells,which produce glucagon, delta cells, which produce somatostatin, and asmall number of PP cells, which produce pancreatic polypeptide. The betacells tend to be in the center of the pancreatic islets, while the alphacells tend to occupy the periphery. The beta cells generally constitute60-70% of the islets, the alpha cells 20-25%, and the delta cellsapproximately 10%. Gap junctions exist between neighboring islet cells,permitting the ready flow of molecules and electrical currents betweencells. If these gap junctions are disrupted, insulin secretion ismarkedly reduced. Islet cell clusters function better as electrical thanbiochemical syncytia.

Under normal circumstances, insulin is secreted by the beta cells inresponse to an elevated level of plasma glucose via the following steps.The transportation of glucose across the beta cell membrane isfacilitated by a specific transporter molecule known as GLUT-2. Onceinside the beta cell, the enzyme glucokinase causes glucose tophosphorylate (i.e., to take-up or combine with phosphoric acid or aphosphorus-containing group), which prevents its efflux. High levels ofglucose and glucose-6-phosphate within the cell lead to a rapid increasein the ratio of adenosine triphosphate (ATP) to adenosine diphosphate(ADP), which leads directly to the closure of ATP-sensitivetransmembrane potassium ion (K+) channels. This prevents the normalefflux of K+ from the beta cell, and the cell depolarizes.Voltage-regulated calcium ion (Ca++) channels open in response to thisdepolarization, allowing an influx of Ca++. Elevated intracellular Ca++leads to activation of protein kinases and ultimately to fusion ofinsulin-containing secretory granules with the beta cell membrane, thusleading to exocytosis of insulin into the systemic circulation. Thisentire sequence occurs within one minute of exposure to elevated glucoselevels.

Insulin is a hormone that serves a variety of functions. Its primaryaction is to potentiate the uptake of glucose from the bloodstream bymuscle and adipose tissue. It also promotes conversion of glucose to astorage form (i.e., glycogen) in the liver and to fat in adipose tissue.These actions serve to decrease the circulating level of glucose.

Glucagon is released primarily under conditions of hypoglycemia, and ittends to have effects opposite those of insulin. Release of glucagon isalso promoted by alpha-adrenergic neurotransmitters, and it is inhibitedby beta-adrenergic neurotransmitters, cholinergic neurotransmitters, andinsulin.

Somatostatin secretion is stimulated by glucose, glucagon,beta-adrenergic neurotransmitters, cholinergic neurotransmitters, and anumber of other chemical factors; its release is inhibited by insulinand by alpha-adrenergic neurotransmitters. Somatostatin tends to inhibitthe release of both insulin and glucagon.

Secretion of insulin may also be modulated by other neural and chemicalfactors. Parasympathetic stimulation and the consequent release ofacetylcholine tends to increase the secretion of insulin. Sympatheticstimulation produces competing effects, as beta-adrenergicneurotransmitters tend to increase insulin secretion whilealpha-adrenergic neurotransmitters tend to decrease insulin secretion.Insulin secretion is also increased by a number of other factors,including K+, Ca++, arginine, lysine, glucagon, glucagon-like peptide 1,gastric inhibitory peptide (GIP), secretin, cholecystokinin (CCK), andbeta-3-agonists. Insulin secretion is also decreased by a number ofother factors, including somatostatin, galanin, pancreastatin, andleptin.

Parasympathetic Stimulation

A significant body of research exists describing the influence ofparasympathetic activity on insulin secretion by the pancreatic betacells. Parasympathetic nerve stimulation in the dog produces a markedincrease in insulin secretion and a moderate increase in glucagonsecretion. In addition, parasympathetic activation produces increasedinsulin and glucagon secretion in proportion to pulse frequency, whileinhibiting somatostatin release. Cholinergic neurotransmitters, whichare the neurotransmitters most commonly secreted by parasympatheticnerve fibers, were found to be responsible for this influence. However,findings also suggest that a noncholinergic neurotransmitter(s) may alsobe involved in parasympathetic regulation of pancreatic hormonesecretion.

The dependence of insulin and glucagon secretion on parasympatheticnerve stimulation parameters was quantified in 1981 by Holst, et al., ina study on young pigs. [Holst, et al. “Nervous control of pancreaticendocrine secretion in pigs.” Acta. Physiol. Scand.; 1981 January;111(1):1-7.] The responses depended on the frequency of the stimulation.The threshold frequency was less than 1 Hz and the maximum response wasreached at 8-12 Hz. Further, with maximal stimulation, the quantity ofinsulin secreted was comparable to the amount released during glucosestimulation.

However, both the insulin and the glucagon response were criticallydependent on the blood glucose concentration during the stimulation. Theglucagon response was inversely correlated to blood glucose, whereas theinsulin response was positively correlated to blood glucose atconcentrations above 4.5 mmol/L. Below this glucose concentration, therewas no detectable insulin response to parasympathetic nerve stimulation,and above 8.0 mmol/L there was no glucagon response to parasympatheticnerve stimulation. Secretion of glucagon and insulin was maintained forup to 30 minutes of stimulation.

In 1987, Berthoud demonstrated that the response of abdominal andthoracic organs to parasympathetic nerve activity depends on thefrequency of electrical stimulation of the nerve. [Berthoud, et al.“Characteristics of gastric and pancreatic responses to vagalstimulation with varied frequencies: evidence for different fibercalibers?” Journ. Auton. Nerv. Syst.; 1987 April; 19(1):77-84.] Thefrequency-response curves show distinctly different profiles for thegastric, pancreatic, and cardiovascular responses: acid secretion wasnear maximal at less than 1 Hz, insulin and glucagon responses were nearmaximal at approximately 3 Hz, and cardiovascular responses were nearmaximal at approximately 15 Hz. These results suggest that the gastricparietal cells may be innervated by small C-fiber caliber axons, and thepancreatic islets, by axons in the large C-fiber or small B-fiber range.Alternatively, these findings could reflect differences in neuron andend organ coupling. These findings also suggest the feasibility offrequency selection to maximize parasympathetically mediated responseswhile minimizing any secondary responses.

The specific parasympathetic pathways innervating the pancreatic isletsare known. Three branches of the vagus nerve mediate both insulin andglucagon release: the posterior gastric branch (198% and 117% increasefrom basal for insulin and glucagon, respectively), the anterior gastricbranch (177% insulin increase and 104% glucagon increase), and thehepatic branch (103% insulin increase and 60% glucagon increase). Incontrast, unreliable and insignificant hormonal responses were producedby the electrical stimulation of fibers projecting from two otherbranches of the vagus nerve: the posterior celiac branch (12% insulinincrease and 12% glucagon increase) and the accessory celiac branch (15%insulin increase and 31% glucagon increase).

Sympathetic Stimulation

The sympathetic nervous system also exerts a significant influence oninsulin and glucagon secretion by the pancreatic islets. The sympatheticsplanchnic nerve, arising from the paraspinal sympathetic trunks, is theprimary sympathetic influence on the pancreas. Its primaryneurotransmitter is norepinephrine, which activates alpha-adrenergic andbeta-1-adrenergic receptors, but has relatively little influence onbeta-2-adrenergic receptors.

In 1990, Kurose thoroughly investigated the effects of electricalstimulation of the left splanchnic nerve on insulin, somatostatin, andglucagon secretion from the isolated, perfused rat pancreas. [Kurose, etal. “Mechanism of sympathetic neural regulation of insulin,somatostatin, and glucagon secretion.” Am. Journ. Physiol.; 1990January; 258(1 Pt 1):E220-7.] Splanchnic nerve stimulation (SNS)performed by square-wave impulses produced a 10-fold increase innorepinephrine. Both insulin and somatostatin output in the presence of16.7 mM glucose were inhibited during SNS by 85% and 56% of the basalvalue, respectively. Glucagon output in the presence of 5.5 mM glucosewas increased 20-fold by SNS.

Kurose, et al. further demonstrated that activation of differentsubtypes of sympathetic (adrenergic) receptors, specificallyalpha-adrenergic and beta-adrenergic, produced significantly differentresults on insulin, glucagon, and somatostatin secretion. Propranolol, anonselective beta-adrenoceptor antagonist, further decreased insulin andsomatostatin output during SNS, while the glucagon response to SNStended to be enhanced, although not significantly, by simultaneousinfusion of propranolol.

In contrast, phentolamine, a nonselective alpha-adrenoceptor antagonist,attenuated the SNS-induced inhibition of insulin and somatostatin outputby 50 and 40%, respectively. The SNS-induced glucagon increase wasabolished by phentolamine alone or by phentolamine plus propranolol.With phentolamine plus propranolol, insulin and somatostatin outputremained decreased after SNS.

In 1992, Kurose also found that, in diabetic rats, the sensitivity ofalpha and delta cells to sympathetic neural activation is blunted,whereas the sensitivity of beta cells is enhanced. [Kurose, et al.“Glucagon, insulin and somatostatin secretion in response to sympatheticneural activation in streptozotocin-induced diabetic rats.”Diabetologia; 1992 November; 35(11):1035-41.]

Later studies confirmed that inhibition of insulin secretion by thesympathetic nervous system may be mediated by norepinephrine acting onalpha-2-adrenoceptors and also by a nonadrenergic cotransmitter thatmaintains transmission despite norepinephrine deficiency. It waspostulated that the nonadrenergic cotransmitter(s) act, at least partly,via the opening of ATP-modulated K+ channels. Its action may beantagonized by glibenclamide, and its release can be prevented by theneuronal blocking agent bretylium.

Beta Cell Transplantation

Since a common defect in all types of diabetes is a defect or a loss ofpancreatic islet beta cells, transplantation of such cells has beenexplored as a possible therapy for diabetes. It has been demonstratedthat grafted islets are not reinnervated, and thus are not under neuralcontrol. However, it was also demonstrated that these grafted isletsrelease insulin in response to increased levels of glucose, and that atleast one parasympathetic agonist, methacholine, causes the graftedislets to increase insulin secretion.

Stimulation Examples

Relatively low-frequency electrical stimulation (i.e., less than about50-100 Hz) has been demonstrated to excite neural tissue, leading toincreased neural activity. Similarly, excitatory neurotransmitters,agonists thereof, and agents that act to increase levels of anexcitatory neurotransmitter(s) have been demonstrated to excite neuraltissue, leading to increased neural activity. Inhibitoryneurotransmitters have been demonstrated to inhibit neural tissue,leading to decreased neural activity; however, antagonists of inhibitoryneurotransmitters and agents that act to decrease levels of aninhibitory neurotransmitter(s) have been demonstrated to excite neuraltissue, leading to increased neural activity.

Relatively high-frequency electrical stimulation (i.e., greater thanabout 50-100 Hz) is believed to have an inhibitory effect on neuraltissue, leading to decreased neural activity. Similarly, inhibitoryneurotransmitters, agonists thereof, and agents that act to increaselevels of an inhibitory neurotransmitter(s) have an inhibitory effect onneural tissue, leading to decreased neural activity. Excitatoryneurotransmitters have been demonstrated to excite neural tissue,leading to increased neural activity; however, antagonists of excitatoryneurotransmitters and agents that act to decrease levels of anexcitatory neurotransmitter(s) inhibit neural tissue, leading todecreased neural activity.

Electrical stimulation has been proposed for treating diabetes. However,the electrical stimulation was applied either to pancreatic beta cells(U.S. Pat. Nos. 5,919,216 and 6,093,167) or to the vagus nerve (U.S.Pat. No. 5,231,988) to treat endocrine disorders. In addition, thesedevices require significant surgical procedures for placement ofelectrodes, catheters, leads, and/or processing units. These devices mayalso require an external apparatus that needs to be strapped orotherwise affixed to the skin.

FIG. 1 is a schematic of the autonomic nervous system, FIG. 2 depictsthe innervation of areas and structures in the vicinity of the pancreas,and FIGS. 3A, 3B, and 3C are different views of nerves in the vicinityof the pancreas. The pancreas 100 receives parasympathetic input fromvarious branches of the vagus nerve 110. These vagal nerve branchesinclude the celiac branches 112, the anterior hepatic branch 114, theanterior gastric branch 116, and the posterior gastric branch 117.

Sympathetic input from the spinal cord 120 travels through right andleft thoracic ganglia of the sympathetic trunks 122. These ganglia aredesignated, for example, RT5 for the right fifth thoracic ganglion ofthe right sympathetic trunk 124 and LT9 for the left ninth thoracicganglion of the left sympathetic trunk 126. Signals are carried from thethoracic region of the sympathetic trunks by the right greater, lesser,and least splanchnic nerves 130 and the left greater, lesser, and leastsplanchnic nerves 132. Sympathetic signals travel through a number ofganglia: the celiac ganglia 140, the aorticorenal ganglia 142, the supermesenteric ganglion 144, the inferior mesenteric ganglion 146, and thephrenic ganglion 148.

The pancreas is comprised mostly of acini and islets of Langerhans.Acini comprise over 80% of the gland. Each acinus is lined withwedge-shaped acinar cells. Acinar cells are the site of production andsecretion of the digestive enzymes.

Capillaries allow hormones from the islet cells to reach the acinarcells. Islets of Langerhans are scattered irregularly throughout thepancreas and contain the islet cells, which are responsible forsecreting the endocrine hormones: insulin, glucagon, somatostatin, andpancreatic polypeptide. The insulin-secreting beta cells comprise about60-70% of the islet. They are surrounded by a mantle ofglucagon-secreting alpha cells, somatostatin-secreting delta cells, andpancreatic polypeptide-secreting PP cells. The various cells of theislets are separated from one another by a rich capillary network.

The present invention provides electrical and/or drug stimulation to atleast one or more of the above mentioned areas as a treatment fordiabetes. Herein, stimulating drugs comprise medications, anestheticagents, synthetic or natural hormones, neurotransmitters, cytokines andother intracellular and intercellular chemical signals and messengers,and the like. In addition, certain neurotransmitters, hormones, andother drugs are excitatory for some tissues, yet are inhibitory to othertissues. Therefore, where, herein, a drug is referred to as an“excitatory” drug, this means that the drug is acting in an excitatorymanner, although it may act in an inhibitory manner in othercircumstances and/or locations. Similarly, where an “inhibitory” drug ismentioned, this drug is acting in an inhibitory manner, although inother circumstances and/or locations, it may be an “excitatory” drug. Inaddition, stimulation of an area herein may include stimulation of cellbodies and axons in the area.

In some alternatives, an implantable signal generator and electrode(s)and/or an implantable pump and catheter(s) are used to deliverelectrical stimulation and/or one or more stimulating drugs to thetarget area(s). One or more electrodes are surgically implanted toprovide electrical stimulation, and/or one or more catheters aresurgically implanted to infuse the stimulating drug(s).

In some embodiments, electrical stimulation is provided by one or moresystem control units (SCUs) that are small, implantable stimulators,referred to herein as microstimulators. The microstimulators of thepresent invention may be similar to or of the type referred to as BION®devices (see FIGS. 4A, 4B, and 4C). The following documents describevarious details associated with the manufacture, operation and use ofBION implantable microstimulators, and are all incorporated herein byreference:

Application/Patent/ Filing/Publication Publication No. Date Title U.S.Pat. No. 5,193,539 Issued Implantable Microstimulator Mar. 16, 1993 U.S.Pat. No. 5,193,540 Issued Structure and Method of Manufacture of anImplantable Mar. 16, 1993 Microstimulator U.S. Pat. No. 5,312,439 IssuedImplantable Device Having an Electrolytic Storage May 17, 1994 ElectrodeU.S. Pat. No. 5,324,316 Issued Implantable Microstimulator Jun. 28, 1994U.S. Pat. No. 5,405,367 Issued Structure and Method of Manufacture of anImplantable Apr. 11, 1995 Microstimulator PGT Publication PublishedBattery-Powered Patient Implantable Device WO 98/37926 Sept. 3, 1998 PCTPublication Published System of Implantable Devices For Monitoringand/or WO 98/43700 Oct. 8, 1998 Affecting Body Parameters PCTPublication Published System of Implantable Devices For Monitoringand/or WO 98/43701 Oct. 8, 1998 Affecting Body Parameters U.S. Pat. No.6,051,017 Issued Apr. 18, 2000 Improved Implantable Microstimulator andSystems (App. No. 09/077,662) (filed May 29, 1998) Employing SamePublished Micromodular Implants to Provide Electrical StimulationSeptember, 1997 of Paralyzed Muscles and Limbs, by Cameron, et al.,published in IEEE Transactions on Biomedical Engineering, Vol. 44, No.9, pages 781-790.

As shown in FIGS. 4A, 4B, and 4C, microstimulator SCUs 160 may include anarrow, elongated capsule 152 containing electronic circuitry 154connected to electrodes 172 and 172′, which may pass through the wallsof the capsule at either end. Alternatively, electrodes 172 and/or 172′may be built into the case and/or arranged on a catheter 180 (FIG. 4B)or at the end of a lead, as described below. As detailed in thereferenced patents, electrodes 172 and 172′ generally comprise astimulating electrode (to be placed close to the target tissue) and anindifferent electrode (for completing the circuit). Other configurationsof microstimulator SCU 160 are possible, as is evident from theabove-referenced patent publications, and as described in more detailherein.

Certain configurations of implantable microstimulator SCU 160 aresufficiently small to permit placement in or adjacent to the structuresto be stimulated. For instance, in these configurations, capsule 152 mayhave a diameter of about 4-5 mm, or only about 3 mm, or even less thanabout 3 mm. In these configurations, capsule length may be about 25-35mm, or only about 20-25 mm, or even less than about 20 mm. The shape ofthe microstimulator may be determined by the structure of the desiredtarget, the surrounding area, and the method of implantation. A thin,elongated cylinder with electrodes at the ends, as shown in FIGS. 4A,4B, and 4C, is one possible configuration, but other shapes, such ascylinders, disks, spheres, and helical structures, are possible, as areadditional electrodes, infusion outlets, leads, and/or catheters.

Microstimulator SCU 160, when certain configurations are used, may beimplanted with a surgical insertion tool such as the tool specificallydesigned for the purpose, or may be injected (e.g., via a hypodermicneedle). Alternatively, microstimulator SCU 160 may be implanted viaconventional surgical methods, or may be inserted using other endoscopicor laparoscopic techniques. A more complicated surgical procedure may berequired for fixing the microstimulator in place.

The external surfaces of microstimulator SCU 160 may advantageously becomposed of biocompatible materials. Capsule 152 may be made of, forinstance, glass or ceramic to provide a hermetic package that willexclude water vapor but permit passage of electromagnetic fields used totransmit data and/or power. Electrodes 172 and 172′ may be made of anoble or refractory metal, such as platinum, iridium, tantalum,titanium, niobium or their alloys, in order to avoid corrosion orelectrolysis which could damage the surrounding tissues and the device.

In certain embodiments of the instant invention, microstimulator SCU 160comprises two, leadless electrodes. However, either or both electrodes172 and 172′ may alternatively be located at the ends of short, flexibleleads as described in U.S. patent application No. 09/624,130, filed Jul.24, 2000, which is incorporated herein by reference in its entirety. Theuse of such leads permits, among other things, electrical stimulation tobe directed more locally to targeted tissue(s) a short distance from thesurgical fixation of the bulk of microstimulator SCU 160, while allowingmost elements of the microstimulator to be located in a more surgicallyconvenient site. This minimizes the distance traversed and the surgicalplanes crossed by the device and any lead(s). In most uses of thisinvention, the leads are no longer than about 150 mm.

As mentioned earlier, stimulation is provided in accordance with theteachings of the present invention by electrical stimulation and/or oneor more stimulating drugs. The invention includes one or more systemcontrol units (SCUs). In the case of electrical stimulation only, SCUsinclude a microstimulator and/or an implantable pulse/signal generator(IPG), or the like. In the case of drug infusion only, an SCU comprisesan implantable pump or the like. In cases requiring both electricalstimulation and drug infusion, more than one SCU may be used.Alternatively, when needed and/or desired, an SCU provides bothelectrical stimulation and one or more stimulating drugs.

As depicted in FIG. 5, some embodiments of SCU 160 may be (but are notnecessarily) implanted in a surgically-created shallow depression oropening, such as in the abdomen or above the buttock. In severalembodiments, SCU 160 conforms to the profile of surrounding tissue(s)and/or bone(s), and is small and compact. This may minimize upwardpressure applied to the skin, which pressure may result in skin erosionor infection. In various embodiments, SCU 160 has a diameter of about 75mm, or only about 65 mm, or even less than about 55 mm. In theseconfigurations, SCU thickness may be approximately 10-12 mm, or evenless than about 10 mm.

As seen in the embodiments depicted in FIG. 5, one or more electrodeleads 170 and/or catheters 180 attached to SCU 160 run subcutaneously,for instance, in a surgically-created shallow groove(s) or channel(s) orin a fascial plane(s). Recessed placement of the SCU and the lead(s)and/or catheter(s) may decrease the likelihood of erosion of overlyingskin, and may minimize any cosmetic impact.

In embodiments such as in FIG. 5, electrode(s) 172 are carried on lead170 having a proximal end coupled to SCU 160. The lead contains wireselectrically connecting electrodes 172 to SCU 160. SCU 160 containselectrical components 154 that produce electrical stimulation pulsesthat travel through the wires of lead 170 and are delivered toelectrodes 172, and thus to the tissue surrounding electrodes 172. Toprotect the electrical components inside SCU 160, some or all of thecase of the SCU may be hermetically sealed. For additional protectionagainst, e.g., impact, the case may be made of metal (e.g. titanium) orceramic, which materials are also, advantageously, biocompatible. Inaddition, SCU 160 may be configured to be Magnetic Resonance Imaging(MRI) compatible.

In some alternatives, the electrical stimulation may be provided asdescribed in International Patent Application Serial NumberPCT/US00/20294 (the '294 application), filed Jul. 26, 2000, whichapplication is incorporated herein by reference in its entirety. The'294 application is directed to a “Rechargeable Spinal Cord StimulatorSystem.” In other alternatives, the electrical stimulation may be asprovided in International Patent Application Serial NumberPCT/US01/04417, filed Feb. 12, 2001, which application is alsoincorporated herein by reference in its entirety. The '417 applicationis directed to a “Deep Brain Stimulation System for the Treatment ofParkinson's Disease or Other Disorders”.

In the case of treatment alternatively or additionally constituting druginfusion, SCU 160 may contain at least one pump 162 for storing anddispensing one or more drugs through infusion outlet(s) 182 and/orcatheter(s) 180 into a predetermined site. When a catheter is used, itincludes at least one infusion outlet 182, usually positioned at leastat a distal end, while a proximal end of the catheter is connected toSCU 160.

According to some embodiments of the invention, such as described in thepreviously referenced PCT applications and as depicted in FIG. 5, atleast one lead 170 is attached to SCU 160, via a suitable connector 168,if necessary. Each lead includes at least two electrodes 172, and mayinclude as many as sixteen or more electrodes 172. Additional leads 170′and/or catheter(s) 180′ may be attached to SCU 160. Hence, FIG. 5 shows(in phantom lines) a second catheter 180′, and a second lead 170′,having electrodes 172′ thereon, also attached to SCU 160. Similarly, theSCUs 160 of FIGS. 4A, 4B, and 4C have outlets 182, 182′ for infusing astimulating drug(s) and electrodes 172, 172′ for applying electricalstimulation.

Lead(s) 170 of certain embodiments of the present invention may be lessthan about 5 mm in diameter, or even less than about 1.5 mm in diameter.Electrodes 172, 172′ on leads 170, 170′ may be arranged as an array, forinstance, as two or more collinear electrodes, or even as four or morecollinear electrodes, or they may not be collinear. A tip electrode mayalso be supplied at the distal end of one or more leads. In someembodiments, SCU 160 is programmable to produce either monopolarelectrical stimulation, e.g., using the SCU case as an indifferentelectrode, or bipolar electrical stimulation, e.g., using one of theelectrodes of the electrode array as an indifferent electrode. Someembodiments of SCU 160 have at least four channels and drive up tosixteen electrodes or more.

SCU 160 (which herein refers to IPGs, implantable pumps, IPG/pumpcombinations, microstimulators for drug and/or electrical stimulation,other alternative devices described herein, and the like) contains, whennecessary and/or desired, electronic circuitry 154 for receiving dataand/or power from outside the body by inductive, radio frequency (RF),or other electromagnetic coupling. In some embodiments, electroniccircuitry 154 includes an inductive coil for receiving and transmittingRF data and/or power, an integrated circuit (IC) chip for decoding andstoring stimulation parameters and generating stimulation pulses (eitherintermittent or continuous), and additional discrete electroniccomponents required to complete the electronic circuit functions, e.g.capacitor(s), resistor(s), coil(s), and the like.

SCU 160 also includes, when necessary and/or desired, a programmablememory 164 for storing a set(s) of data, stimulation, and controlparameters. Among other things, memory 164 may allow electrical and/ordrug stimulation to be adjusted to settings that are safe andefficacious with minimal discomfort for each individual. Specificparameters may provide therapy for various types and degrees of severityof diabetes. For instance, some patients may respond favorably tointermittent stimulation, while others may require continuous treatmentfor relief. In some embodiments, electrical and drug stimulationparameters are controlled independently. In various embodiments, theyare coupled, e.g., electrical stimulation is programmed to occur onlyduring drug infusion.

In addition, parameters may be chosen to target specific tissues and toexclude others. For example, parameters may be chosen to increase neuralactivity in specific neural populations and to decrease neural activityin others. As another example, relatively low frequency neurostimulation(i.e., less than about 50-100 Hz) typically has an excitatory effect onsurrounding neural tissue, leading to increased neural activity, whereasrelatively high frequency neurostimulation (i.e., greater than about50-100 Hz) may have an inhibitory effect, leading to decreased neuralactivity. Similarly, excitatory neurotransmitters (e.g., acetylcholine),agonists thereof, and agents that increase levels of an excitatoryneurotransmitter(s) (e.g., edrophonium) generally have an excitatoryeffect on neural tissue, while inhibitory neurotransmitters (e.g.,gamma-aminobutyric acid, a.k.a. GABA), agonists thereof, and agents thatact to increase levels of an inhibitory neurotransmitter(s) generallyhave an inhibitory effect. However, antagonists of inhibitoryneurotransmitters (e.g., bicuculline) and agents that act to decreaselevels of an inhibitory neurotransmitter(s) have been demonstrated toexcite neural tissue, leading to increased neural activity. Similarly,excitatory neurotransmitter antagonists (e.g. atropine) and agents thatdecrease levels of excitatory neurotransmitters may inhibit neuralactivity.

Some embodiments of SCU 160 also include a power source and/or powerstorage device 166. Possible power options for a stimulation device ofthe present invention, described in more detail below, include but arenot limited to an external power source coupled to the stimulationdevice, e.g., via an RF link, a self-contained power source utilizingany means of generation or storage of energy (e.g., a primary battery, arechargeable battery such as a lithium ion battery, an electrolyticcapacitor, or a super- or ultra-capacitor), and if the self-containedpower source is replenishable or rechargeable, means of replenishing orrecharging the power source (e.g., an RF link).

In embodiments such as shown in FIG. 5, SCU 160 includes a rechargeablebattery as a power source/storage device 166. The battery is recharged,as required, from an external battery charging system (EBCS) 192,typically through an inductive link 194. In these embodiments, and asexplained more fully in the earlier referenced PCT applications, SCU 160includes a processor and other electronic circuitry 154 that allow it togenerate stimulation pulses that are applied to a patient 208 throughelectrodes 172 and/or outlet(s) 182 in accordance with a program andstimulation parameters stored in programmable memory 164. Stimulationpulses of drugs include various types and/or rates of infusion, such asintermittent infusion, infusion at a constant rate, and bolus infusion.

According to certain embodiments of the invention, an SCU operatesindependently. According to various embodiments of the invention, an SCUoperates in a coordinated manner with other SCU(s), other implanteddevice(s), or other device(s) external to the patient's body. Forinstance, an SCU may control or operate under the control of anotherimplanted SCU(s), other implanted device(s), or other device(s) externalto the patient's body. An SCU may communicate with other implanted SCUs,other implanted devices, and/or devices external to a patient's bodyvia, e.g., an RF link, an ultrasonic link, or an optical link.Specifically, an SCU may communicate with an external remote control(e.g., patient and/or physician programmer) that is capable of sendingcommands and/or data to an SCU and that may also be capable of receivingcommands and/or data from an SCU.

For example, some embodiments of SCU 160 of the present invention may beactivated and deactivated, programmed and tested through a hand heldprogrammer (HHP) 200 (which may also be referred to as a patientprogrammer and may be, but is not necessarily, hand held), a clinicianprogramming system (CPS) 202 (which may also be hand held), and/or amanufacturing and diagnostic system (MDS) 204 (which may also be handheld). HHP 200 may be coupled to SCU 160 via an RF link 195. Similarly,MDS 204 may be coupled to SCU 160 via another RF link 196. In a likemanner, CPS 202 may be coupled to HHP 200 via an infra-red link 197; andMDS 204 may be coupled to HHP 200 via another infra-red link 198. Othertypes of telecommunicative links, other than RF or infra-red may also beused for this purpose. Through these links, CPS 202, for example, may becoupled through HHP 200 to SCU 160 for programming or diagnosticpurposes. MDS 204 may also be coupled to SCU 160, either directlythrough the RF link 196, or indirectly through IR link 198, HHP 200, andRF link 195.

In certain embodiments, using for example, a BION microstimulator(s) asdescribed in the above referenced patents, and as illustrated in FIG. 6,the patient 208 switches SCU 160 on and off by use of controller 210,which may be hand held. Controller 210 operates to control SCU 160 byany of various means, including sensing the proximity of a permanentmagnet located in controller 210, sensing RF transmissions fromcontroller 210, or the like.

External components of various embodiments for programming and providingpower to SCU 160 are also illustrated in FIG. 6. When it is required tocommunicate with SCU 160, patient 208 is positioned on or near externalappliance 220, which appliance contains one or more inductive coils 222or other means of communication (e.g., RF transmitter and receiver).External appliance 220 is connected to or is a part of externalelectronic circuitry appliance 230 which may receive power 232 from aconventional power source. External appliance 230 contains manual inputmeans 238, e.g., a keypad, whereby the patient 208 or a caregiver 242may request changes in electrical and/or drug stimulation parametersproduced during the normal operation of SCU 160. In these embodiments,manual input means 238 includes various electro-mechanical switchesand/or visual display devices that provide the patient and/or caregiverwith information about the status and prior programming of SCU 160.

Alternatively or additionally, external electronic appliance 230 isprovided with an electronic interface means 246 for interacting withother computing means 248, such as by a serial interface cable orinfrared link to a personal computer or to a telephone modem or thelike. Such interface means 246 may permit a clinician to monitor thestatus of the implant and prescribe new stimulation parameters from aremote location.

The external appliance(s) may be embedded in a cushion, pillow, mattresscover, or garment. Other possibilities exist, including a belt or otherstructure that may be affixed to the patient's body or clothing.

In order to help determine the strength and/or duration of electricalstimulation and/or the amount and/or type(s) of stimulating drug(s)required to produce the desired effect, in some embodiments, a patient'sresponse to and/or need for treatment is sensed. For example, electricalactivity of the brain (e.g., EEG), nerve activity (e.g., ENG), muscleactivity (e.g., EMG), gastric distention, or other activity may besensed. Additionally or alternatively, one or more neurotransmitterlevels and/or their associated breakdown product levels, hormone levels,cytokine levels, or other substances, such as ketone, glucose,electrolyte, enzyme, and/or medication levels and/or changes in these orother substances in the blood plasma or local interstitial fluid, may besensed.

For example, when electrodes of SCU 160 are implanted adjacent to atleast one of the celiac ganglia 140, a stimulating electrode of SCU 160,or other sensing means, may be used to sense changes in insulin levelresulting from the electrical and/or drug stimulation applied to the atleast one celiac ganglion 140. (As used herein, “adjacent” or “near”means as close as reasonably possible to targeted tissue, includingtouching or even being positioned within the tissue, but in general, maybe as far as about 150 mm from the target tissue.)

Alternatively, an “SCU” dedicated to sensory processes communicates withan SCU that provides the stimulation pulses. The implant circuitry 154may, if necessary, amplify and transmit these sensed signals, which maybe digital or analog. Other methods of determining the requiredelectrical and/or drug stimulation include measuring impedance,acidity/alkalinity (via a pH sensor),body mass, and other methodsmentioned herein, and others that will be evident to those of skill inthe art upon review of the present disclosure. The sensed informationmay be used to control stimulation parameters in a closed-loop manner.

For instance, in several embodiments of the present invention, a firstand second “SCU” are provided. The second “SCU” periodically (e.g. onceper minute) records glucose level (or the level of insulin or of someother substance, or an amount of electrical activity, etc.), which ittransmits to the first SCU. The first SCU uses the sensed information toadjust electrical and/or drug stimulation parameters according to analgorithm programmed, e.g., by a physician. For example, the amplitudeof electrical stimulation may be increased in response to decreasedinsulin levels. In some alternatives, one SCU performs both the sensingand stimulating functions, as discussed in more detail presently.

While an SCU 160 may also incorporate means of sensing diabetes orsymptoms or other prognostic or diagnostic indicators of diabetes, e.g.,via levels of a neurotransmitter or hormone, it may alternatively oradditionally be desirable to use a separate or specialized implantabledevice to record and telemeter physiological conditions/responses inorder to adjust electrical stimulation and/or drug infusion parameters.This information may be transmitted to an external device, such asexternal appliance 220, or may be transmitted directly to implantedSCU(s) 160. However, in some cases, it may not be necessary or desiredto include a sensing function or device, in which case stimulationparameters are determined and refined, for instance, by patientfeedback, or the like.

Thus, it is seen that in accordance with the present invention, one ormore external appliances may be provided to interact with SCU 160, andmay be used to accomplish, potentially among other things, one or moreof the following functions:

Function 1: If necessary, transmit electrical power from the externalelectronic appliance 230 via appliance 220 to SCU 160 in order to powerthe device and/or recharge the power source/storage device 166. Externalelectronic appliance 230 may include an automatic algorithm that adjustselectrical and/or drug stimulation parameters automatically whenever theSCU(s) 160 is/are recharged.

Function 2: Transmit data from the external appliance 230 via theexternal appliance 220 to SCU 160 in order to change the parameters ofelectrical and/or drug stimulation produced by SCU 160.

Function 3: Transmit sensed data indicating a need for treatment or inresponse to stimulation from SCU 160 (e.g., glucose level, electricalactivity of the brain, nerve activity, muscle activity, neurotransmitterlevels, levels of neurotransmitter breakdown products, impedance,acidity/alkalinity, medication levels, hormone levels, or otheractivity) to external appliance 230 via external appliance 220.

Function 4: Transmit data indicating state of the SCU 160 (e.g., batterylevel, drug level, stimulation parameters, etc.) to external appliance230 via external appliance 220.

By way of example, a treatment modality for diabetes may be carried outaccording to the following sequence of procedures:

1. An SCU 160 is implanted so that its electrodes 172 and/or infusionoutlet 182 are located in or near one or both celiac ganglia 140. Ifnecessary or desired, electrodes 172′ and/or infusion outlet(s) 182′ mayadditionally or alternatively be located in or adjacent to otherautonomic ganglia and/or nerves, such as branches of the vagus orsplanchnic nerves, and/or may be located adjacent islets of Langerhansor pancreatic alpha, beta, and/or delta cells.

2. Using Function 2 described above (i.e., transmitting data) ofexternal electronic appliance 230 and external appliance 220, SCU 160 iscommanded to produce a series of inhibitory electrical stimulationpulses, possibly with gradually increasing amplitude, and possibly whileinfusing gradually increasing amounts of a parasympathetic agonist,e.g., methacholine, into naturally occurring and/or transplantedpancreatic beta cells.

3. After each stimulation pulse, or at some other predefined interval,any change in glucose and/or insulin level resulting from the electricaland/or drug stimulation is sensed, for instance, by one or moreelectrodes 172 and/or 172′. These responses are converted to data andtelemetered out to external electronic appliance 230 via Function 3.

4. From the response data received at external appliance 230 from SCU160, the stimulus threshold for obtaining a response is determined andis used by a clinician 242 acting directly 238 or by other computingmeans 248 to transmit the desired electrical and/or drug stimulationparameters to SCU 160 in accordance with Function 2.

5. When patient 208 desires to invoke electrical stimulation and/or druginfusion, patient 208 employs controller 210 to set SCU 160 in a statewhere it delivers a prescribed stimulation pattern from a predeterminedrange of allowable stimulation patterns.

6. To cease electrical and/or drug stimulation, patient 208 employscontroller 210 to turn off SCU 160.

7. Periodically, the patient or caregiver recharges the powersource/storage device 166 of SCU 160, if necessary, in accordance withFunction 1 described above (i.e., transmit electrical power).

For the treatment of any of the various types and degrees of severity ofdiabetes, it may be desirable to modify or adjust the algorithmicfunctions performed by the implanted and/or external components, as wellas the surgical approaches, in ways that would be obvious to skilledpractitioners of these arts. For example, in some situations, it may bedesirable to employ more than one SCU 160, each of which could beseparately controlled by means of a digital address. Multiple channelsand/or multiple patterns of electrical and/or drug stimulation mightthereby be programmed by the clinician and controlled by the patient inorder to deal with complex or multiple diseases, symptoms, ordysfunctions.

In some embodiments discussed earlier, SCU 160, or a group of two ormore SCUs, is controlled via closed-loop operation. A need for and/orresponse to stimulation is sensed via SCU 160, or by an additional SCU(which may or may not be dedicated to the sensing function), or byanother implanted or external device.

If necessary, the sensed information is transmitted to SCU 160. In someembodiments, the parameters used by SCU 160 are automatically adjustedbased on the sensed information. Thus, the electrical and/or drugstimulation parameters are adjusted in a closed-loop manner to providestimulation tailored to the need for and/or response to the electricaland/or drug stimulation.

For instance, as shown in the example of FIG. 7, a first SCU 160,implanted beneath the skin of the patient 208, provides a firstmedication or substance; a second SCU 160′ provides a second medicationor substance; and a third SCU 160″ provides electrical stimulation viaelectrodes 172 and 172′. As mentioned earlier, the implanted devices mayoperate independently or may operate in a coordinated manner with othersimilar implanted devices, other implanted devices, or other devicesexternal to the patient's body, as shown by the control lines 262, 263and 264 in FIG. 7. That is, in accordance with certain embodiments ofthe invention, the external controller 250 controls the operation ofeach of the implanted devices 160, 160′ and 160″. According to variousembodiments of the invention, an implanted device, e.g. SCU 160, maycontrol or operate under the control of another implanted device(s),e.g. SCU 160″ and/or SCU 160″. That is, a device made in accordance withthe invention may communicate with other implanted stimulators, otherimplanted devices, and/or devices external to a patient's body, e.g.,via an RF link, an ultrasonic link, an optical link, or the like.Specifically, as illustrated in FIG. 7, SCU 160, 160′, and/or 160″, madein accordance with the invention, may communicate with an externalremote control (e.g., patient and/or physician programmer 250) that iscapable of sending commands and/or data to implanted devices and thatmay also be capable of receiving commands and/or data from implanteddevices.

A drug infusion stimulator made in accordance with the invention mayincorporate communication means for communicating with one or moreexternal or site-specific drug delivery devices, and, further, may havethe control flexibility to synchronize and control the duration of drugdelivery. The associated drug delivery device typically provides afeedback signal that lets the control device know it has received andunderstood commands. The communication signal between the implantedstimulator and the drug delivery device may be encoded to prevent theaccidental or inadvertent delivery of drugs by other signals.

An SCU made in accordance with the invention thus incorporates, in someembodiments, first sensing means 268 for sensing therapeutic effects,clinical variables, or other indicators of the state of the patient,such as EEG, ENG, EMG, gastric distention, impedance, pH, body mass, orthe like. The stimulator additionally or alternatively incorporatessecond means 269 for sensing neurotransmitter levels and/or theirassociated breakdown product levels, medication levels and/or other druglevels, insulin, hormone, glucose, ketone, electrolytes, enzyme, and/orcytokine levels and/or changes in these or other substances in the bloodplasma or local interstitial fluid. The stimulator additionally oralternatively incorporates third means 270 for sensing electricalcurrent levels and/or waveforms supplied by another source of electricalenergy. Sensed information may be used to control infusion and/orelectrical parameters in a closed loop manner, as shown by control lines266, 267, and 265. Thus, sensing means may be incorporated into a devicethat also includes electrical and/or drug stimulation, or the sensingmeans (that may or may not have stimulating means) may communicate thesensed information to another device(s) with stimulating means.

According to certain embodiments of the invention, the electrodes of anSCU are implanted adjacent to pancreatic beta cells in order to effectmodulation of insulin secretion for therapy in diabetic patients. Thesemay be beta cells of the patent or may be transplanted beta cells. AnSCU effects depolarization of these beta cells through the applicationof an appropriate electrical pulse. It is known in the art how to applyan appropriate electrical pulse to depolarize, or to hyperpolarize, acell. As described above, voltage-regulated calcium ion (Ca++) channelswill open in response to cellular depolarization, allowing an influx ofCa++. Elevated intracellular Ca++ leads to activation of protein kinasesand ultimately to fusion of insulin-containing secretory granules withthe beta cell membrane, thus leading to exocytosis of insulin into thesystemic circulation.

Additionally or alternatively, an SCU may be implanted with electrodesadjacent to alpha and/or delta cells. By applying an electrical pulse tohyperpolarize alpha cells, the secretion of glucagon by alpha cells isinhibited. By applying an electrical pulse to hyperpolarize delta cells,the secretion of somatostatin by delta cells is inhibited. Inhibition ofglucagon and/or somatostatin prevents their inhibition of insulinsecretion.

An SCU may also/instead apply an electrical pulse to hyperpolarize betacells. This effectively inhibits the secretion of insulin, which istherapeutic during periods of hypoglycemia. Additionally oralternatively, an SCU may apply an electrical pulse to depolarize alphacells, which increases the secretion of glucagon, and/or delta cells,which increases the secretion of somatostatin. The secretion of insulinis inhibited by the presence of glucagon and/or somatostatin. Again,this is therapeutic during periods of hypoglycemia.

Selective stimulation of beta, alpha, and delta cells is possible due tosegregation of cells in the pancreatic islets. More than one SCU 160 ormultiple electrodes 172, 172′ may be implanted to achievehyperpolarization (or depolarization) of a larger number of specificislet cells.

According to certain embodiments of the invention, stimulation may beapplied to sympathetic and/or parasympathetic nerves and/or ganglia thatinnervate the pancreatic islets. As mentioned earlier, differentparameters of electrical stimulation may result in significantlydifferent responses from autonomic nerve fibers, and parameters may bechosen to target specific neural populations and to exclude others.Relatively low frequency neurostimulation (i.e., less than about 50-100Hz) tends to have an excitatory effect on neural tissue, whereasrelatively high frequency neurostimulation (i.e., greater than about50-100 Hz) tends to have an inhibitory effect. Thus, electricalstimulation may be used to excite or to inhibit neural activity.

In some embodiments of the present invention, stimulation increasesexcitement of parasympathetic input to the pancreatic beta cells, forinstance, the posterior gastric, anterior gastric, celiac, and/orhepatic branches of the vagus nerve, thereby increasing insulinsecretion and treating hyperglycemia in a diabetic patient.Additionally, as described above, the response of beta cells, and ofabdominal and thoracic organs, to parasympathetic activity depends inpart on the frequency of electrical stimulation. Stimulation may beapplied at frequencies that maximize pancreatic islet cell response,while limiting the stimulation of the heart, stomach, and other organsof the gastrointestinal tract. For example, electrical stimulation ofparasympathetic targets may be applied at approximately 3-12 Hz, or atapproximately 3-8 Hz, or at approximately 3-5 Hz.

In certain embodiments of the present invention, stimulation decreasesexcitement of the sympathetic input to the pancreatic beta cells. Forinstance, inhibitory stimulation (i.e., greater than about 50-100 Hz)may be applied to one or more of the right and left, greater, lesser,and least splanchnic nerves 130 and 132 and/or to one or more of thesympathetic ganglia innervating the pancreas (i.e., celiac ganglia 140,aorticorenal ganglia 142, super mesenteric ganglion 144, inferiormesenteric ganglion 146, phrenic ganglion 148, and ganglia of theparaspinal sympathetic trunks 124 and 126). This sympathetic inhibitionmay increase insulin secretion, thus treating hyperglycemia in adiabetic patient. In addition, this sympathetic inhibition is likely toinhibit secretion of glucagon, thereby preventing glucagon frominhibiting insulin secretion and insulin effects on target tissues.

During periods of hypoglycemia, parasympathetic input may be inhibitedand/or sympathetic input may be activated in order to decrease insulinsecretion and increase glucagon secretion. In this case, variousembodiments of the invention provide relatively high-frequencystimulation (i.e., greater than about 50-100 Hz) to parasympatheticnerves innervating the pancreas, such as to the posterior gastric,anterior gastric, celiac, and hepatic branches of the vagus nerve,thereby decreasing insulin secretion and/or increasing glucagonsecretion and treating a patient with hypoglycemia.

Additionally or alternatively, relatively low-frequency stimulation(i.e. less than about 50-100 Hz) may be applied to sympathetic nervesand/or ganglia innervating the pancreas to inhibit insulin secretion.This excitatory stimulation may be applied to one or more of the rightand left, greater, lesser, and least splanchnic nerves 130 and 132and/or to one or more sympathetic ganglia innervating the pancreas(i.e., celiac ganglia 140, aorticorenal ganglia 142, super mesentericganglion 144, inferior mesenteric ganglion 146, phrenic ganglion 148,and ganglia of the paraspinal sympathetic trunks 124 and 126). Inaddition, this excitatory sympathetic stimulation is likely to activatesecretion of glucagon, thereby further inhibiting insulin secretion.

In addition or instead of electrical stimulation, one or more SCUs maydeliver excitatory or inhibitory substances to pancreatic islet cells.As described earlier, one or more discharge portion(s) 182/182′,possibly positioned on one or more catheters 180/180′, may be surgicallyimplanted at one or more pancreatic islets, pancreatic beta cellsgraft(s), parasympathetic nerves, and/or sympathetic nerves and/organglia.

In some embodiments, to treat hyperglycemia, an SCU(s) may releasesubstances into an islet(s) and/or graft(s) that increase insulinsecretion, including glucose, K+, Ca++, arginine, lysine, acetylcholine,cholinergic agonist(s), beta-adrenergic agonist(s), alpha-adrenergicantagonist(s), glucagon, glucagon-like peptide 1, gastric inhibitorypeptide (GIP), secretin, cholecystokinin (CCK), and beta-3-agonist(s).Additionally or alternatively, an SCU(s) may release substances into anislet(s) and/or graft(s) that inhibit glucagon secretion, includingalpha-adrenergic antagonists, glucose, insulin, and somatostatin.

In several embodiments, hyperglycemia may be treated by releasingsubstances in or near parasympathetic synapses to excite parasympatheticactivity. These excitatory substances include at least one of aparasympathetic neurotransmitter agonist(s) (e.g., acetylcholine), amedication that increases the level of an excitatory neurotransmitter(e.g., edrophnium), an excitatory hormone agonists(s), an inhibitoryneurotransmitter antagonist(s), an inhibitory hormone antagonist(s),and/or the like. One or more of these substances may be released in ornear one or more of the parasympathetic ganglia and/or sites ofpostganglionic parasympathetic synapses.

In certain embodiments, hyperglycemia may be treated by releasingsubstances in or near sympathetic synapses to inhibit sympatheticactivity. These inhibitory substances include at least one of asympathetic neurotransmitter antagonist(s) (e.g., mecamylamine acting ona sympathetic ganglion/ganglia, and/or phentolamine and/or propranololacting on a postganglionic synapse(s)), a medication that decreases thelevel of a sympathetic neurotransmitter (e.g., metyrosine), aninhibitory hormone agonist(s), an excitatory hormone antagonist(s),and/or the like. Some of these substances are known as adrenoceptorantagonist medications and/or autonomic ganglion-blocking medications.One or more of the above substances may be released in or near one ormore of the celiac ganglia 140, aorticorenal ganglia 142, supermesenteric ganglion 144, inferior mesenteric ganglion 146, phrenicganglion 148, ganglia of the paraspinal sympathetic trunks 124 and 126,and/or at sites of postganglionic sympathetic synapses.

In various embodiments, to treat hypoglycemia, an SCU(s) may releasesubstances into an islet(s) and/or graft(s) that inhibit insulinsecretion, including alpha-adrenergic agonists, cholinergic antagonists,beta-adrenergic antagonists, somatostatin, galanin, pancreastatin, andleptin. Additionally or alternatively, an SCU(s) may release substancesthat promote glucagon secretion, including alpha-adrenergic agonists,arginine, and alanine.

In some embodiments, hypoglycemia may be treated by releasing substancesin or near parasympathetic synapses to inhibit parasympathetic activity.These inhibitory substances include at least one of an inhibitoryneurotransmitter agonist(s), a medication that increases the level of aninhibitory neurotransmitter, an inhibitory hormone agonist(s), anparasympathetic neurotransmitter antagonist(s) (e.g., atropine acting ona postganglionic synapses(s) and/or mecamylamine acting on aparasympathetic ganglion/ganglia), an excitatory hormone antagonist(s),and/or the like. Some of these substances are known ascholinoceptor-blocking medications and/or autonomic ganglion-blockingdrugs. One or more of the above substances may be released in or nearone or more of the parasympathetic ganglia and/or sites ofpostganglionic parasympathetic synapses.

In several embodiments, hypoglycemia may be treated by releasingsubstances in or near sympathetic synapses to excite sympatheticactivity. These substances include at least one of an sympatheticneurotransmitter agonist(s) (e.g., norepinephrine), a medication thatincreases the level of an excitatory neurotransmitter, an excitatoryhormone agonists(s) (e.g., epinephrine), an inhibitory neurotransmitterantagonist(s), an inhibitory hormone antagonist(s), and/or the like.Some of these substances are known as adrenoceptor-activating and/orsympathomimetic medications. One or more of these substances may bereleased in or near one or more of the celiac ganglia 140, aorticorenalganglia 142, super mesenteric ganglion 144, inferior mesenteric ganglion146, phrenic ganglion 148, ganglia of the paraspinal sympathetic trunks124 and 126, and/or at sites of postganglionic sympathetic synapses.

In certain embodiments, sensing means described earlier may be used toorchestrate first the activation of SCU(s) targeting one or moreautonomic and/or pancreatic tissues, and then, when appropriate, theSCU(s) targeting another area(s) and/or by a different means.Alternatively, this orchestration may be programmed, and not based on asensed condition.

Additional potential (but not necessary) uses of the present inventioninclude, but are not limited to, application to diabetes prevention, asmentioned earlier.

While the invention herein disclosed has been described by means ofspecific embodiments and applications thereof, numerous modificationsand variations could be made thereto by those skilled in the art withoutdeparting from the scope of the invention set forth in the claims.

What is claimed is:
 1. A method of modulating pancreatic endocrinesecretions of a patient, comprising: implanting at least one systemcontrol unit in the body of a patient, wherein the at least one unitcontrols the delivery of at least one stimulus to at least one type ofpancreatic cell affecting pancreatic endocrine secretions; and applyingthe at least one stimulus to the at least one type of pancreatic cell inorder to hyperpolarize the at least one type of pancreatic cell andthereby modulate at least one pancreatic endocrine secretion; whereinthe at least one type of pancreatic cell is an alpha cell and whereinthe hyperpolarization inhibits secretion of glucagon.
 2. A method ofmodulating pancreatic endocrine secretions of a patient, comprising:implanting at least one system control unit in the body of a patient,wherein the at least one unit controls the delivery of at least onestimulus to at least one type of pancreatic cell affecting pancreaticendocrine secretions; and applying the at least one stimulus to the atleast one type of pancreatic cell in order to hyperpolarize the at leastone type of pancreatic cell and thereby modulate at least one pancreaticendocrine secretion; wherein the at least one type of pancreatic cell isa delta cell and wherein the hyperpolarization inhibits secretion ofsomatostatin.
 3. A method of modulating pancreatic endocrine secretionsof a patient, comprising: implanting at least one system control unit inthe body of a patient, wherein the at least one unit controls thedelivery of at least one stimulus to at least one type of pancreaticcell affecting pancreatic endocrine secretions; and applying the atleast one stimulus to the at least one type of pancreatic cell in orderto depolarize the at least one type of pancreatic cell to therebyincrease secretion of a substance that inhibits insulin secretion. 4.The method of claim 3, wherein the at least one type of pancreatic cellis an alpha cell and wherein the depolarization increases secretion ofglucagon.
 5. The method of claim 3 wherein the at least one type ofpancreatic cell is a delta cell and wherein the depolarization increasessecretion of somatostatin.
 6. A method of modulating pancreaticendocrine secretions of a patient, comprising: implanting at least onesystem control unit in the body of a patient, wherein the at least oneunit controls the delivery of simulation to at least one parasympathetictissue innervating the pancreas; and applying the stimulation to the atleast one parasympathetic tissue in order to minimize stimulation ofgastrointestinal structures and the heart while maximizing stimulationof pancreatic beta cells, whereby insulin secretion is modulated.
 7. Themethod of claim 6 wherein the stimulation is applied to at least one ofthe posterior gastric, anterior gastric, celiac, and hepatic branches ofthe vagus nerve.
 8. The method of claim 6 further comprising applyingthe stimulation to the at least one parasympathetic tissue in order toincrease insulin secretion.
 9. The method of claim 8 wherein the atleast one system control unit is connected to at least two electrodes,and wherein the stimulation is electrical stimulation applied via the atleast two electrodes at a frequency of about 3-12 Hz.
 10. The method ofclaim 6 further comprising applying the simulation to the at least oneparasympathetic tissue in order to decrease insulin secretion.
 11. Themethod of claim 10 wherein the at least one system control unit isconnected to at least two electrodes, and wherein the stimulation iselectrical stimulation applied via the at least two electrodes at afrequency of greater than about 50 Hz.
 12. The method of claim 10wherein the simulation is drug simulation and wherein at least one of acholinoceptor-blocking medication and an autonomic ganglion-blockingmedication is applied to the parasympathetic tissue.
 13. A method ofmodulating pancreatic endocrine secretions of a patient, comprising:implanting at least one system control unit in the body of a patient,wherein the at least one unit controls the delivery of stimulation to atleast one sympathetic tissue innervating the pancreas; and applying thestimulation to the at least one sympathetic tissue in order to modulateat least one pancreatic endocrine secretion; wherein the at least onesympathetic tissue is at least one of the ganglia of the paraspinalsympathetic trunks, cellac ganglia, aorticorenal ganglia, supermesenteric ganglion, inferior mesenteric ganglion, phrenic ganglion,left greater splanchnic nerve, left lesser splanchnic nerve, left leastsplanchnic nerve, right greater splanchnic nerve, right lessersplanchnic nerve, and right least splanchnic nerve.
 14. The method ofclaim 13 further comprising sensing a condition and using the sensedcondition to automatically determine the stimulation to apply.
 15. Themethod of claim 13 wherein the stimulation inhibits sympathetic input tothe pancreas, whereby glucagon secretion is reduced.
 16. The method ofclaim 15 wherein the at least one system control unit is connected to atleast two electrodes, and wherein the stimulation is electricalstimulation delivered via the at least two electrodes at a frequency ofgreater than about 50 Hz.
 17. The method of claim 15 wherein thestimulation is drug stimulation and wherein at least one of anadrenoceptor antagonist medication and an autonomic ganglion-blockingmedication is applied to the sympathetic tissue.
 18. The method of claim13 wherein the stimulation excites sympathetic input to the pancreas,whereby glucagon secretion is increased.
 19. The method of claim 18wherein the at least one system control unit is connected to at leasttwo electrodes, and wherein the stimulation is electrical stimulationdelivered via the at least two electrodes at a frequency of less thanabout 100 Hz.
 20. The method of claim 18 wherein the stimulation is drugstimulation and wherein at least one of an adrenoceptor-activatingmedication and a sympathomimetic medication is applied to thesympathetic tissue.
 21. A method of modulating pancreatic endocrinesecretions of a patient, comprising: implanting at least one systemcontrol unit in the body of a patient, wherein the at least one unitcontrols the delivery of drug stimulation to at least one area affectingpancreatic endocrine secretions; and applying the drug stimulation tothe at least one area in order to modulate at least one pancreaticendocrine secretion; wherein the at least one system control unit isconnected to at least one catheter, and wherein the stimulating drug isapplied via the at least one catheter to at least one pancreatic isletor graft to increase insulin secretion, and wherein the drug is at leastone of K+, Ca++, arginine, lysine, acetylcholine, a cholinergic agonist,a beta-adrenergic agonist, an alpha-adrenergic antagonist, glucagon-likepeptide 1, gastric inhibitory peptide, secretin, cholecystokinin, and abeta-3-agonist.
 22. The method of claim 21 further comprising sensing acondition and using the sensed condition to automatically determine thestimulation to apply.
 23. A method of modulating pancreatic endocrinesecretions of a patient, comprising: implanting at least one systemcontrol unit in the body of a patient, wherein the at least one unitcontrols the delivery of drug stimulation to at least one area affectingpancreatic endocrine secretions; and applying the drug stimulation tothe at least one area in order to modulate at least one pancreaticendocrine secretion; wherein the at least one system control unit isconnected to at least one catheter, and wherein the stimulating drug isapplied via the at least one catheter to at least one pancreatic isletor graft to inhibit insulin secretion, and wherein the drug is at leastone of an alpha-adrenergic agonist, a chollnergic antagonist, abeta-adrenergic antagonist, galanic, oancreastatin, and leptin.
 24. Themethod of claim 23 further comprising sensing a condition and using thesensed condition to automatically determine the stimulation to apply.25. A method of modulating pancreatic endocrine secretions of a patient,comprising: implanting at least one system control unit in the body of apatient, wherein the at least one unit controls the delivery of drugstimulation to at least one area affecting pancreatic endocrinesecretions; and applying the drug stimulation to the at least one areain order to modulate at least one pancreatic endocrine secretion;wherein the at least one system control unit is connected to at leastone catheter, and wherein the stimulating drug is applied via the atleast one catheter to at least one pancreatic islet or graft to increaseglucagon secretion, and wherein the drug is at least one of analpha-adrenergic agonist, arginine, and alanine.
 26. The method of claim25 further comprising sensing a condition and using the sensed conditionto automatically determine the stimulation to apply.
 27. A method ofmodulating pancreatic endocrine secretions of a patient, comprising:implanting at least one system control unit in the body of a patient,wherein the at least one unit controls the delivery of drug stimulationto at least one area effecting pancreatic endocrine secretions; andapplying the drug stimulation to the at least one area in order tomodulate at least one pancreatic endocrine secretion; wherein the atleast one system control unit is connected to at least one catheter, andwherein the stimulating drug is applied via the at least one catheter toat least one pancreatic islet or graft to inhibit glucagon secretion,and wherein the drug is at least one of an alpha-adrenergic antagonist,glucose, and insulin.
 28. The method of claim 27 further comprisingsensing a condition and using the sensed condition to automaticallydetermine the stimulation to apply.